The present invention relates to the field of diagnostic methods and apparatus for detecting endometriosis in a patient. More specifically, the present invention relates to a non-surgical method and apparatus for detecting endometriosis.
Endometriosis is defined as the presence of endometrial tissue in aberrant locations of the body, usually in the pelvis.
There are no techniques for the confirmation of this disease other than the pathological assessment of the tissue that is removed or biopsied during a surgical procedure. Magnetic Resonance Imaging (“MRI”) is helpful in the detection but the standard of care still requires histological confirmation. The pathological definition is based on the recognition that there are endometrial glands and endometrial stroma located in deposits of the organs involved. By definition, these tissues and organs are outside the uterine cavity. The glands and stroma have the same characteristics as those located in the uterine lining the so-called endometrium.
Notably, these tissues are also associated with hormonally-induced changes that tend to be similar to those identified in the uterus. These patterns in the uterus are called proliferative and secretary, depending on the activity of the glands in response to ovarian hormonal stimulation. During the early proliferative phase, the dominant hormonal stimulation is estradiol leading to an increasing proliferative appearance in the glands. After ovulation, the dominant pattern is secretory due to the presence of both estradiol and progesterone. It should be noted that the endometriotic tissues are not always identified as having exactly parallel histological appearances as those in the uterus.
There is an additional confounder to this situation. The surgeon making a decision to biopsy the disease does so on the basis of the visual appearance of the tissues. A variety of appearances of the endometriotic tissues are possible from a simple vesicle to highly pigmented lesions of the tissues due to the deposition of iron as hemosiderin and ferritin directly into the tissues. Often there is a discrepancy in the diagnosis because the visual appearance of the disease observed by the surgeon is not always confirmed by the pathologist. This is also present in the ovary where endometriosis can be the cause of bloody or chocolate cysts.
There are other causes of such a chocolate cyst, such as a corpus luteum cyst, or any other cyst that has undergone hemorrhagic degeneration. Non-endometriotic chocolate cysts tend to resolve over a relatively short span of time, unlike ovarian endometriomas.
Unless there is evidence of endometriosis elsewhere such as located in the vagina where it can be visualized easily during a pelvic examination (which is very unusual), the diagnosis requires a surgical procedure to be undertaken, although MRI may be helpful.
The disease is generally quite tightly associated with the reproductive life span of women. It only occurs in primates that menstruate. The disease is thought to have a major part of its origin from the implantation of endometrial tissues that have implanted on normal tissue during retrograde menstruation. Alternatively, it is thought there may be a process of metaplasia in which the cells of the particular tissue undergo metaplasia to form the endometrial glands. One single method has not explained all of the manifestations of the disease.
There is increasing interest in the disease as one of the chronic illnesses associated with both a genetic and an environmental interaction. Some putative genetic markers have been identified but the situation remains one of intense interest. The environmental aspects have included the possibility that environmental toxins can affect the immune system in such a manner that the retrograde-passed endometrial tissues are not removed by the body's usual defense mechanisms. These are most significantly associated with the exposure to dioxin in subhuman primates, although there are conflicting results in terms of severe human exposures. A more robust statement has recently been reported in the medical literature, as noted below.
Although there has been a reported increase in the incidence and prevalence of this disease, this may be an ascertainment bias given the greater appreciation of smaller, less differentiated lesions more recently and the greater impact of medical therapy for infertility and pelvic pain over the past few decades. It is theorized, however, that increased exposures to priority chemicals over the past 40 years might have an important contributory role in the disease.
Several reports have suggested that iron may be playing a role in the pathophysiology of the condition. Iron is present in the tissues and the peritoneal fluid. It can be identified through histological techniques using Prussian blue staining. Iron is also measured in the peritoneal fluid that is often present to varying degrees in the pelvis. It can be identified as iron, ferritin and transferrin in concentrations that are similar to those associated with the serum or higher.
The role that iron is playing in the disease is uncertain at present. There is hypothetically a role of the disease in the generation of tissue injury and fibrosis through the generation of adhesions through the Fenton reaction. This well known biochemical reaction uses the electron configuration of the iron atom to generate singlet oxygen in the presence of peroxide and organic molecules. It results in the degradation of these organic chemicals. However, there is controversy surrounding the activities of this theory because of the varied responses to the measurements of the products of lipid peroxidation in the peritoneal cavity.
More recent findings have implicated the tissue metallothionenes in the alteration of the normal tissue architecture. Also, there have been developments in the use of magnetic resonance imaging to detect the disease and provide an alternative to surgical therapy in the staging of the disease. It should be noted, however, that the measurement of iron in the peritoneal fluid of women should be considered an experimental procedure.
The symptoms and signs of the disease are consistent with alterations in the anatomy owing to scarring and deformities of the normal tissues. Patients with the disease are noted to have commonly experienced infertility and pelvic pain. In both cases, the actual mechanisms are not clearly understood. In some cases, the infertile subjects have minimal disease and the cause of the infertility is considered to be unknown. In more advanced cases, the disease disrupts tubal and ovarian function such that there is a physical barrier to the co-location of the egg and sperm.
Similarly, in subjects with pelvic pain, there can be severe pain and disability that can be associated with minimal amounts of endometriosis. In other more advanced cases the disease takes on a definite invasive and nodular appearance that progresses during the reproductive years until menopausal reduction in hormonal support tends to lessen the impact of the subject's experience of pain.
The actual processes of the disease are not fully understood. Thus, the direct approach to the disease is not apparent at present but is directed to the symptoms of this fundamentally mysterious condition. Approaches to the care of patients have been identified through expert panels and consensus conferences. In general, the common approach is to undertake a medical approach through the use of certain medications and turn to surgery when this is unsuccessful. It should be noted, however, the disease is very diverse in its presentation and individualization of care is important.
From a medical perspective, there is an approach to develop some degree of control over the menstrual cycle. The oral contraceptive is commonly used as it limits the amount of menstrual bleeding experienced by many women, which has a direct impact on the degree of pain experienced. Also, some feel this drug limits further deposition of implants and provides a progestogenic environment that allows the tissue to heal.
More significant progestogenic action can be achieved through the use of depot forms of progesterone. The use of GnRH agonists has been commonplace. These drugs initiate a pseudo menopause such that the ovarian production of hormones is greatly reduced to levels that would be identified at menopause. One additional drug, Danazol, is a steroid with mild androgenic actions that has also been used to suppress the disease.
These drugs and their approaches have been used in the management of both infertility and pelvic pain. Of course, in the area of infertility, there has been a move to new reproductive technologies to bypass the known or unknown factors in the pelvis and permit fertilization of the embryo.
Magnetic resonance imaging (MRI) has been used to explore the appearance of the disease using low-energy radio frequency radiation, magnetic fields and computers to create 2-D images based on the varying local environments of water molecules in the body. The appearance of endometriomas or endometriotic cysts of the ovary on MRI is variable and depends on the concentration of iron and protein in the fluid from blood degradation. Most endometriomas have a gross appearance of “chocolate cysts,” representing highly concentrated blood products.
MRI demonstrates these endometriomas as cystic masses with very high signal on T1-weighted images and very low signal on T2-weighted images. This low signal intensity on the T2-weighted images is termed “shading” and occasionally occurs in a gradient from higher to lower signal intensity. This pattern of signal intensity results from the high iron concentration in the endometrioma and is rarely seen in other masses of any type.
Multiple high-signal lesions, usually in the ovaries, on T1-weighted images also are highly suggestive of endometriosis. Peritoneal implants initially are small serosal lesions and usually escape detection. Larger fibrotic implants of endometriosis are seen on MRI as spiculated nodules of very low signal intensity on T2-weighted images. These occur commonly in the cul-de-sac and less commonly on the bladder dome, rectum, umbilicus, or in pelvic surgical scars. Dilated fallopian tubes occasionally are seen on MRI in patients with endometriosis; these demonstrate high signal intensity on T1-weighted images, indicative of bloody fluid.
MRI also can demonstrate the complications of endometriosis. Bowel obstructions and hydronephrosis occasionally can be seen. Since longer imaging times are required for MRI, anti-peristaltic medication can improve visualization of bowel. In one study, MRI showed a sensitivity of 90-92%/o and a specificity of 91-98% for the diagnosis of endometrioma in patients with adnexal masses. Thus, MRI is an accurate technique in distinguishing endometriomas from other masses. Other studies have indicated the combined use of MRI and laparoscopy are complementary and formulate the best currently available diagnostic approach.
Surgical therapy is frequently undertaken either through diagnostic or therapeutic laparoscopy or through laparotomy. With advances in the development of laparoscopic surgery, there is a decrease in the need for laparotomy but there is still a significant amount of surgery being undertaken, particularly, oophorectomy and hysterectomy. One additional concern is the fact that many subjects with the disease have repeated laparoscopy procedures that eventually culminate in a hysterectomy.
To reduce the number of laparoscopy procedures on a patient for diagnostic purposes, it is, therefore, desirable to have a non-surgical diagnostic method and apparatus for detecting the presence of endometriosis in the patient.
Contemporary findings on pelvic endometriosis have been reported in the literature as follows:    (1) Cramer D W, Missmer S A. The epidemiology of endometriosis. Ann NY Acad Sci 2002; 955:11-22.    (2) Zondervan K, Barlow D H. Epidemiology of chronic pelvic pain. Baillieres Best Pract Res Clin Obstet Gynaecol 2000; 14(3):403-414.    (3) Zondervan K T, Cardon L R, Kennedy S H. The genetic basis of endometriosis. Curr Opin Obstet Gynecol 2001; 13(3):309-314.    (4) Kennedy S. The genetics of endometriosis. Eur J Obstet Gynecol Reprod Biol 1999; 82(2):129-133.    (5) Kennedy S. Genetics of endometriosis: a review of the positional cloning approaches. Semin Reprod Med 2003; 21(2):111-118.    (6) Kennedy S. The genetics of endometriosis. J Reprod Med 1998; 43(3 Suppl):263-268.    (7) Rier S, Foster W G. Environmental dioxins and endometriosis. Sermin Reprod Med 2003; 21(2):145-154.    (8) Rier S, Foster W G. Environmental dioxins and endometriosis. Toxicol Sci 2002; 70(2):161-170.    (9) Rier S E. The potential role of exposure to environmental toxicants in the pathophysiology of endometriosis. Ann NY Acad Sci 2002; 955:201-212.    (10) Eskenazi B, Mocarelli P, Warner M, Samuels S, Vercellini P, Olive D et al. Serum dioxin concentrations and endometriosis: a cohort study in Seveso, Italy. Environ Health Perspect 2002; 110(7):629-634.    (11) Eskenazi B, Mocarelli P, Warner M, Samuels S, Vercellini P, Olive D et al. Seveso Women's Health Study: a study of the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on reproductive health. Chemosphere 2000; 40(9-11):1247-1253.    (12) Guo S W. The Link between Exposure to Dioxin and Endometriosis: A Critical Reappraisal of Primate Data. Gynecol Obstet Invest 2004; 57(3):157-173.    (13) Van Langendonckt A, Casanas-Roux F, Donnez J. Oxidative stress and peritoneal endometriosis. Fertil Steril 2002; 77(5):861-870.    (14) Van Langendonckt A, Casanas-Roux F. Donnez J. Iron overload in the peritoneal cavity of women with pelvic endometriosis. Fertil Steril 2002; 78(4):712-718.    (15) Polak G, Rola R, Gogacz M, Koziol-Montewka M, Kotarski J. Malonyldialdehyde and total antioxidant status in the peritoneal fluid of infertile women. Ginekol Pol 1999; 70(3):135-140.    (16) Osteen K G, Yeaman G R, Bruner-Tran K L. Matrix metalloproteinases and endometriosis. Semin Reprod Med 2003; 21(2):155-164.    (17) Osteen K G, Bruner-Tran K L, Keller N R, Eisenberg E. Progesterone-mediated endometrial maturation limits matrix metalloproteinase (MMP) expression in an inflammatory-like environment: a regulatory system altered in endometriosis. Ann NY Acad Sci 2002; 955:37-47.    (18) Zanardi R, Del Frate C, Zuiani C, Bazzocchi M. Staging of pelvic endometriosis based on MRI findings versus laparoscopic classification according to the American Fertility Society. Abdom Imaging 2003; 28(5):733-742.    (19) Olive D L, Pritts E A. The treatment of endometriosis: a review of the evidence. Ann NY Acad Sci 2002; 955:360-372.    (20) Martin D C. Research aspects of endometriosis surgery. Ann NY Acad Sci 2002; 955:353-359.    (21) Togashi, K.; Nishimura, K.; Kimura, I.; Tsuda, Y.; Yamashita, K.; Shibata, T.; Nakano, Y.; Konishi, J.; Konishi, I.; Morin T. Endometrial cysts: diagnosis with MR imaging. Radiology 180:73-78.